The invention relates to substituted nortropanes and their use to image: a) dopamine-transporter-containing neurons, particularly in connection with diagnosis and study of certain neurodegenerative disorders; and b) cocaine receptors.
There is a need for diagnostic agents and markers of neurogenerative disorders such as Parkinson's disease. For example, exclusion at an early stage of Parkinson's disease as the cause of symptoms may be useful information in diagnosing other conditions. Moreover, early diagnosis of Parkinson's disease can facilitate the introduction of putative prophylactic drug therapy (e.g., deprenyl) prior to the onset of more severe symptoms. See, Kaufman and Madras (1991) Synapse 9:43-49. Detection of nerve cell depletion in the presymptomatic phase in an animal model of Parkinson's disease would also be useful, e.g., when using the model to evaluate therapies for Parkinson's disease. See, Hantraye et al. (1992) Neuro Reports 3:265-268; and Hahtraye et al. (1992) Soc. Neurosci. Abstra. 18:935.
There is a particular need for diagnostic agents and markers of neurogenerative disorders that selectively target a dopamine transporting protein (the dopamine transporter) in preference to another protein known as the serotonin transporter. In normal brain tissue, the dopamine:serotonin transporter density ratio is approximately 10:1. In certain neurodegenerative disorders, such as Parkinson's disease, nerve cells that produce dopamine (and on which the dopamine transporter is located) undergo severe depletion, while serotonin nerve cells are less affected. The dopamine:serotonin transporter ratio can fall to 50% in Parkinson's disease.
Various substances (particularly cocaine and cocaine congeners) are potent inhibitors of dopamine transport in the striatum of the brain because they bind to the dopamine transporter. The more strongly these substances block dopamine transport, the more strongly they bind to sites on the dopamine transporter which have been labeled by [.sup.3 H]cocaine or by a compound known as [.sup.3 H] CFT (also known as [.sup.3 H]WIN 35,428)..sup.1 See, Madras et al., (1989) J. Pharmacol. Exp. Ther. 251:131-141; and Madras et al. (1989) Mol. Pharmacol. 36:518-524. FNT .sup.1 2-carboxymethyl-3-(4-fluorophenyl)tropane.
CFT (WIN 35,428) and similar substances exhibit markedly decreased binding in the Parkinson's diseased brain. See, Madras et al. Soc. Neurosci. Abst. 16:14, 1990; and Kaufman and Madras (1991) Synapse 9:43-49. The hope that these compounds might be Parkinson's markers is further supported by the parallel between loss of binding and loss of dopamine in the diseased brain (Madras et al. Catechol. Symp. 193, 1992).
Dopamine transporter-binding compounds that have been studied include N-allyl-2 carboxymethyl-3.beta.-fluorophenyltropane. See, Madras et al. (1990) Pharmacology, Biochemistry & Behavior 35:949-953; and Milius et al. (1991) J. Med. Chem. 34:1728-1731.
Goodman et al. report (1992) J. Nuclear Med. 33:890) the synthesis of 2-.beta.-carbomethoxy-3-.beta.-(4-chlorophenyl)-8-(.sup.123 I-iodopropene-2yl) nortropane. The selectivity of this analog for the dopamine over the serotonin transporter is not discussed.
CFT or WIN 35,428 is approximately 15 times more selective for the dopamine over the serotonin transporter. The 4-chloro analog is 4-fold selective. See Carroll et al., J. Med. Chem. 35:969 (1992); and Meltzer et al., J. Med. Chem. 36:855-862 (1993).